Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted is molecules are a growing superfamily of 8–14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two:main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C—X—C) and Cys-Cys (C—C) families. These two groups are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
The C—X—C chemokines include several potent chemoattractants and activators of, neutrophils such as interleukin-8 (CXCL8) and neutrophil-activating peptide 2 (CXCL7).
The C—C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils. Examples include human monocyte chemotactic proteins 1–3 (CCL2, CCL7 and CCL8), RANTES (CCL5), eotaxin (CCL11) and the macrophage inflammatory proteins 1α and 1β (CCL3 and CCL4).
There is also a third chemokine family based upon the structural motif Cys-X3-Cys (C—X3—C). This C—X3—C family is distinguished from the C—X—C and C—C families on the basis of having a triple amino acid insertion between the NH-proximal pair of cysteine residues. CX3CL1 (also known as fractalkine) is a potent chemoattractant and activator of microglia in the central nervous system as well as of monocytes, T cells, NK cells and mast cells.
Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors. In particular, the actions of CX3CL1 are mediated by the CX3CR1 receptor.
WO 00/09511 discloses thiazolopyrimidine compounds that are useful as antagonists of receptors linked to the C—X—C and C—C chemokine families, particularly as antagonists of the CXCR2 receptor.
The present invention relates to a group of compounds that are partly within the generic scope of WO 00/09511 but which surprisingly display useful properties as antagonists of the CX3CR1 receptor.